OVERVIEW: What every practitioner needs to know

Are you sure your patient has an infantile hemangioma? What are the typical findings for this disease?

Infantile hemangiomas (IH) are the most common tumor of childhood, with an estimated incidence of 4 to 5%, and up to 10% in Caucasian infants. The majority require anticipatory guidance and expectant management, but an important subset necessitate intervention because of size, location, anticipated residual deformity, threat to vital function (such as vision, feeding, breathing, or voiding/stooling), or associated abnormalities as part of syndromes, such as PHACE syndrome.

Typical findings:

Rapidly proliferating vascular lesion presenting in the first 2 to 4 weeks of life.

Follows a course of nascence at birth, early rapid proliferation for 3 to 5 months, slower late proliferation, up to 9 to 12 months in some, plateau, and involution over a period of years.

Morphology may be superficial (bright red/pink), deep (skin colored to bluish), or mixed (having both superficial and deep components, which is most common).

May also be subdivided based on distribution into a) focal - arising from a single point, b) segmental - occupying an apparent developmental unit, or c) indeterminate - thought to be "sub"-segmental.

Natural history of infantile hemangioma growth

Because they are often not present or nascent (and sometimes mistaken for birth trauma or a bruise) in the immediate neonatal period, they typically are not recognized at the time of discharge from the hospital after birth.

Most IH will double in size in the first 2 months of life.

The majority of IH growth occurs early in life, such that 80% of growth for most IH occurs by 3 months of age and 80% have completed growth by 5 months of age. The proliferative phase tends to be longer in deep IH (those without a pink/red plaque at the surface) and in segmental IH and can last up to 9 to 12 months, but rarely longer than that.

Natural involution occurs over a period of years, with current evidence suggesting that most involution occurs by age 3.5 to 4 years of age, which is in opposition to traditional dogma suggesting that 10% regression occurs per year.

What are important morphologies of IH?

Focal IH are most common, and appear to arise from a single point.

Segmental IH appear to occupy a developmental unit, and have been shown to follow reproducible patterns on the face. They also occur on the limbs, perineum, and trunk.

Facial segmental IH are significantly more likely to develop complications and require treatment than their focal counterparts. Most notably, they can be associated with PHACE(S) syndrome (See below).

Segment 1 involves the lateral forehead, scalp and eye. IH in this location have a higher likelihood of cerebral and cerebrovascular anomalies.

Segment 2 involves the maxillary face. It appears to be less likely to have associated complications.

Segment 3 involves the lower face, and is sometimes referred to as the "beard" distribution. IH in S3 have a higher risk of cardiac anomalies such as aortic coarctation and airway IH.

Segment 4 involves the frontonasal scalp and extends in a narrow strip from the central forehead to the upper lip. Cerebral and cerebrovascular anomalies can also occur.

Segmental perineal IH can be associated with syndromes (outlined below).

Indeterminate IH are not easily classified as focal or segmental, but may in many cases be considered "sub-segmental."

What syndromes are associated with Infantile Hemangioma?

PHACE(S) syndrome is an acronym for a well described neurocutaneous syndrome, and stands for Posterior fossa malformation, Hemangioma, Arterial anomalies, Coarcation of the aorta, Eye abnormalities, Sternal clefting/supraumbilical raphe. The hemangiomas of PHACE(S) tend to be segmental IH located on the face, but truncal and extremity IH have been described as part of the syndrome.

Neurologic complications are the most common and also the most severe potential sequelae of PHACE(S), occurring in up to 50% of affected infants. In addition to static cerebral malformations (such as those of the posterior fossa) and cerebrovascular anomalies including hypoplasia or agenesis of cerebral vessels, progressive stenoses can occur. Arterial ischemic stroke has been reported rarely. Diagnostic criteria were published in 2009.

PHACE(S)-like syndromes are known to occur when segmental IH occur on the lower body, primarily in the lumbosacral area. The most widely accepted name for this syndrome is: LUMBAR - Lower body hemangioma and other cutaneous defects, Urogenital anomalies, Ulceration, Myelopathy, Bony deformities, Anorectal malformations, Arterial anomalies, and Renal anomalies.

What other disease/condition shares some of these symptoms?

IH must be differentiated from other vascular anomalies, including vascular tumors and vascular malformations that present in childhood.

Vascular Tumors Presenting in Childhood

Congenital Hemangiomas (NICH and RICH) -Significantly rarer than IH, the most important distinguishing feature is that congenital hemangiomas, which are divided into "rapidly involuting congenital hemangiomas (RICH)" and "non-involuting congenital hemangiomas (NICH)," are fully formed and at maximum size at birth. There has also been proposal of an intermediate on the spectrum between RICH and NICH, termed PICH (partially involuting congenital hemangioma).

Kaposiform hemangioendothelioma - Typically deeper seated and more blue to violaceous, and are often associated with a consumptive coagulopathy known as the Kasabach-Merritt phenomenon (KMP). Notably, the KMP does NOT occur with IH.

Tufted angioma - Thought to be a milder variant of kaposiform hemangioendothelioma, these tend to be more macular or plaque-like, though have several different appearances.

Pyogenic granuloma - These are acquired and typically are much smaller than the ultimate size of most IH. They tend to be more friable and bleed easily. They often arise at sites of minor trauma and can be seen at any age, but are less likely to arise in early infancy.

Vascular Malformations Presenting in Childhood

Venous, lymphatic, and arteriovenous malformations may not be apparent at birth, making early differentiation sometimes difficult, but vascular malformations tend to grow with the child as s/he grows, and become slowly progressive, though impressive early growth of venous malformations can sometimes occur making distinction from IH more challenging. Venous and lymphatic malformations are "low-flow" on Doppler imaging, which differentiates them from IH, which are "high-flow." Arteriovenous malformations are also "high-flow", but typically are warm to touch, have a palpable thrill, and cause more hemodynamic compromise when large.

What caused this disease to develop at this time?

Risk factors for the development of IH

Low birth weight: The most significant risk factor in the development of IH. For every 500 g decrease in birth weight, the risk of IH development increases 40%.

Prematurity: Often related to low birth weight, but is an important independent risk factor.

Female infants are 2 to 3 times more likely to develop IH. Female sex is the most common risk factor (given that female sex occurs much more commonly than low birth weight).

Chorionic villus sampling and amniocentesis have been suggested as risk factors, but are not a contributing factor in the majority of cases. Studies outside the US have linked lower maternal education and manual labor during pregnancy as risk factors for IH development.

Approximately 15% of patients with IH will have a family history of vascular "lesion," but are at this time thought to be sporadic, and genetics of IH are not well understood.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Laboratory studies are generally unnecessary to diagnose IH, as the diagnosis is made through a combination of history (of onset in early infancy and characteristic rapid growth) and physical exam.

If a specimen is obtained for pathology, which, again, is rarely necessary for diagnosis, special immunohistochemical stains can differentiate IH from other vascular anomalies; the most specific marker is GLUT-1, which is present at all stages of IH growth and should not stain other vascular tumors or malformations. IH will also stain for placental markers such as Lewis Y antigen and merosin.

Would imaging studies be helpful? If so, which ones?

In rare cases, ultrasound is a good distinguishing tool to determine the blood flow through the lesion. Ultrasound showing a high-flow lesion of variable echogenicity, with high vessel density, low resistance and little to no AV shunting is supportive of the diagnosis of IH.

On magnetic resonance imaging (MRI), IH is seen as a homogeneously enhancing soft tissue mass that is T1 isointense, T2 hyperintense, with flow voids in and around it. When used, MRI/magnetic resonance angiography is typically performed to look for underlying cerebral or cerebrovascular anomalies are part of PHACE syndrome. Echocardiogram should be performed as part of the workup of PHACE syndrome. In cases with concern for LUMBAR syndrome, an MRI/MRA of the lumbosacral spine and pelvis should be obtained.

If you are able to confirm that the patient has an IH, what treatment should be initiated?

The great heterogeneity among IH in terms of size, location, rate of growth, and associated symptoms or lack thereof, makes uniform treatment guidelines somewhat difficult.

For the majority of IH, expectant management and anticipatory guidance for parents is all that is needed. However, because the majority of growth occurs early in life, close monitoring is very important as significant changes in size and associated symptoms (e.g., astigmatism), can occur in a matter of weeks.

Disfiguring - areas with high risk for permanent deformity include nose and lip. Any sizeable IH on the face should be considered strongly for possible treatment, given that up to 50% of IH leave behind scar tissue such as fibrofatty residuum, atrophy, and telangiectasias, and may therefore potentially need later surgery during or after involution. Early intervention may obviate the need for future surgery. It is important to note that since the advent of therapy with oral and topical beta-blockers, the most common indication for initiation of medical therapy is risk of disfigurement, rather than functional impairment.

Segmental hemangiomas have a significantly higher risk of associated complications and need for treatment.

Long term treatment may include reconstructive plastic surgery. Surgery is rarely indicated during the proliferative phase except in cases of life threatening IH or those with severe ulceration recalcitrant to medical therapy.

Drug: Propranolol

Dose: 2 to 3 mg/kg/day given in 2 or 3 divided doses.

Advantage: good safety profile, fewer side effects compared to oral corticosteroids, good tolerability, rapid onset of effect (typically within 48 hours, seen as softening and violaceous color change), high response rate (up to 100% in some larger series), useful during proliferative and involutional phases.

Atenolol and nadolol have also been used orally with similar efficacy and side effect profiles.

Drug: Timolol

Dose: 0.5% gel-forming solution or solution used most commonly at a dose of 1 drop to IH surface twice daily (sometimes three times daily).

Advantage: useful for small IH in cosmetically sensitive locations such as the face or for early intervention in the first several weeks of life while awaiting specialist evaluation in concerning cases; useful in adjunct treatment for healing ulcerated IH.

Disadvantage: ineffective in IH with significant bulk and volume; in young infants concern for systemic absorption if applied in large amounts though available evidence and experience does not suggest risk of hypotension, bradycardia, hypoglycaemia, or bronchospasm exists as with systemic therapy. Onset of effect slow; typically up to 8 weeks of treatment needed to discern significant improvement.

Drug: Prednisolone

Dose: 2 to 3 mg/kg/day typically given as a single morning dose or BID.

Advantage: over 40 years of safe use in the treatment of IH, reliable response, generally well tolerated. Though side effects are well known, none are potentially life threatening, in comparison with propranolol.

Second and third line agents include vincristine and interferon alpha. These are required now in very rare situations given the good efficacy of propranolol and prednisolone.

Ulcerated IH require therapy for both pain control and to accomplish healing. The algorithm for care of ulcerated IH begins with conservative wound care with occlusive ointments such as zinc oxide past and petrolatum. Wound dressings such as hydrocolloid or silver impregnated dressings can be helpful. Pulsed dye laser therapy is often employed. Becaplermin gel is sometimes used off-label, but, it should be noted, carries a FDA black-boxed warning. Both propranolol and prednisolone orally may be necessary to accomplish healing. Topical timolol gel forming solution can aid in the healing of ulceration, but care must to taken to monitor for increased absorption across an ulcerated skin barrier.

What are the adverse effects associated with each treatment option?

See above.

What are the possible outcomes of Infantile Hemangioma?

Prognosis for infants with IH is generally excellent, but varies depending on associated symptoms. Approximately half will involute and leave no notable residua. However, in the other half of cases, complete involution does not necessarily signify complete resolution. There is risk of residual fibrofatty scar tissue, persistent telangiectasias and dermal atrophy. In some cases, this becomes less noticeable with growth and age, but surgery and/or pulsed dye laser treatment may later be required.

Periocular IH can result in astigmatism, amblyopia and visual axis occlusion.

Airway compromise can occur in subglottic IH. There is a higher risk of airway involvement in segmental IH involving the lower face (Segment 3.)

Auditory canal compromise is rare, but can occur.

Cardiac compromise is also rare, but is seen most commonly with hepatic IH resulting in congestive heart failure or related to coarctation of the aorta as part of PHACE(S) syndrome.

Nasal tip IH very commonly destroy cartilage of the nasal tip and are a reconstructive surgical challenge.

Ulceration is the most common complication of IH and tends to occur in the first 4 months of life, during the early proliferative phase. Ulceration signifies that the lesion extends at least to the dermis and, therefore, will always leave a scar. Areas at high risk of ulceration include the lip, neck, diaper area, and axillae. The cause of ulceration is not completely known but in many cases involves sites of maceration and friction. Pain with ulceration can be significant and requires immediate therapy (see above).

PHACE(S) and LUMBAR syndromes have potential sequelae related to their associated symptoms.

The risks of propranolol are related to its potential side effects, and the most concerning for very young infants appears to be hypoglycemia; however, with greater experience in using the drug, the risk of hypoglycaemia is reassuringly minimal with appropriate anticipatory guidance to parents/caregivers. It is very important to counsel parents extensively about the importance of regular feeds. If for any reason oral intake is decreased for a period of time, adjustments must be made to the dose of propranolol to avoid this complication. Asymptomatic hypotension and bradycardia are reasonably common; the significance of this is unknown, but likely minimal. It is important to obtain a history of underlying lung disease that could predispose to bronchospasm. Baseline electrocardiogram is recommended to rule out underlying heart block in infants with a personal or family history of arrhythmia, congenital heart disease, or maternal connective tissue disease, according to consensus statement guidelines. The benefits of propranolol are outlined above.

The risks of oral corticosteroids are well known, and must be reviewed with the family at length. However, it is important to emphasize that the vast majority of infants treated for IH tolerated high dose corticosteroids very well. The benefits of prednisolone are outlined above.

What causes this disease and how frequent is it?

IH occur in 4 to 5% of infants overall, and up to 10% of Caucasian non-Hispanic infants. They occur in up to 30% of premature infants.

Most IH occur sporadically, but there are rare reports of autosomal dominant transmission.

How do these pathogens/genes/exposures cause the disease?

Maternal risk factors/exposures related to IH include advanced maternal age, pre-eclampsia, and placenta previa. Infants who are the product of multiple gestation pregnancies have a higher risk of IH. The largest study to date of over 1000 infants with IH found that there was no association with maternal illness during or preceding pregnancy. Tobacco, alcohol, illicit drugs, and prescription drugs do not appear to be more common in cases of IH.

However, one Chinese study reports lower level of maternal education, participation in manual labor, and use of medication around the time of conception present more commonly in patients with IH.

What complications might you expect from the disease or treatment of the disease?

(Consensus guidelines on use of propranolol for IH. Useful information on pre-treatment workup and recommended monitoring and dosing, though it should be noted, it is primarily based on expert opinion rather than Level 1 evidence.)

(This retrospective study details the safe, effective of oral corticosteroids in IH treatment. The authors suggest that despite enthusiasm for propranolol that prednisolone should remain the standard option and should be considered safer.)

Ongoing controversies regarding etiology, diagnosis, treatment

Controversy remains in some small circles about the use of propranolol versus prednisolone for therapy. The lack of comparative trials makes treatment decisions difficult. Propranolol is now overwhelmingly favored as first line therapy, given its better tolerability and safety profile. An improved understanding of the cause of IH is needed along with better understanding of any potential long term effects of beta-blocker therapy, given how much more liberally therapy is offered with propranolol than it was in the past with oral corticosteroids.